HRP20010158A2 - PROCESS FOR PREPARING N,N,6- TRIMETHYL-2-(4-METHYLPHENYL)-IMIDAZO-[1,2-a]-PYRIDINE-3-ACETAMIDE AND SALTS THEREOF - Google Patents

Abstract

It comprises reducing the hydroxy ester of formula (X) by reacting it in DMF and then with an iminium salt of formula (XIII) formed in situ with thionyl chloride and dimethylformamide, and subsequent reduction with an appropriate reducing agent to form the ester of formula (XII), which is then reacted with dimethylamine in a polyhydroxylated solvent medium at an appropriate temperature.

Description

Field of invention

This invention relates to a new process for the preparation of N,N,6-trimethyl-2-(4-methylphenyl)-imidazo-[1,2-a]-pyridine-3-acetamide and its salts.

Background of the invention

N,N,6-trimethyl-2-(4-methylphenyl)-imidazo-[1,2-a]-pyridine-3-acetamide is a substance that has a clinically hypnotic effect [P. Georg and associates - Actual. Chem. Ther. 18, 215 (1990), P. George et al. - Imidazopyridines in sleep disorders - De. J.P. Sauvanet, S.Z. Langer and P.L. Moselli - Raven Press - New York, 1988, p. 11], and it is characterized by the fact that it does not belong to the group of benzodiazepines, which until now have been the basis of most used drugs with the above-mentioned effect.

This substance has the structural formula (I)

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There are procedures for obtaining N,N,6-trimethyl-2-(4-methylphenyl)-imidazo-[1,2-a]-pyridine-3-acetamide of formula (I) [European patents 50563 and 251589 and French patent 2600650] with of which this substance is prepared by the reaction of imidazo-[1,2-a]pyridine (II) and acetal N,N-dimethyl-glyoxamide (formula III),

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where R represents an alkyl group, resulting in a hydroxyamide of formula (IV), without the formation of an ester intermediate.

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Description of the invention

The procedure for obtaining the substance of the structure of the formula (I), which is the object of the patent application, consists of the reaction of 2-amino-5 methylpyridine of the formula (V) with 4-methyl-haloacetophenone of the formula (VI), in order to form 6-methyl-2-2 (4-methylphenyl)-imidazo-[1,2-a]-pyridine of formula (II).

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The first step of the reaction to obtain (VI) from the acid halide of formula (VII), where X represents Cl or Br, is carried out in toluene with the addition of a Lewis acid as a catalyst, such as aluminum chloride or iron(III) chloride.

The temperature must be below 10 °C.

The second stage takes place in an alkaline medium with the addition of a base, such as sodium dicarbonate or potassium dicarbonate, to the above-mentioned solvent, to which an alcohol containing from one to three carbon atoms is also added.

The operating temperature is between 40 and 70 °C.

6-Methyl-2-2(4-methylphenyl)-imidazo-[1,2-a]-pyridine (II) reacts with methylglyoxalate of formula (VIII) or its hemiacetal (IX), resulting in the hydroxyester of formula (X), which is described for the first time in this invention.

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This reaction is carried out with the use of halogenated hydrocarbon solvents such as dichloromethane, chloroform, 1,2-dichloroethane or trichloroethylene at a temperature of 40 to 70 °C.

The removal of the hydroxyl group is performed by substitution using chlorine in the reaction with the iminium salt, which is formed with the help of thionyl chloride and dimethylformamide. The resulting halogenated compound (XI) is not isolated, but reduction is carried out to form the ester (XII).

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It should be noted that compounds (X), (XI) and (XII), obtained in the process of this invention for obtaining compound (I), are new compounds and have not been described in the literature so far.

In order to obtain (XI), a halogenated solvent such as dichloromethane, chloroform, 1,2-dichloroethane is used at a reaction temperature of 0 to 30 °C.

The reaction using (XI) to form (XII) is carried out in the above solvent with the addition of a reducing agent, such as sodium hydrosulfite or sodium sulfoxylate formaldehyde.

The reaction temperature must be between 10 and 50 °C.

By reacting (XII) with dimethylamine in a polyhydroxylated solvent, such as ethylene glycol or propylene glycol, amide (I) is formed.

By dissolving the amide of formula (I) in an alcohol, such as methanol, ethanol or isopropanol, and adding a solution of an acid, such as tartaric acid, oxalic acid or acetic acid in the same solvent, the corresponding salts are formed. The molar ratio of added acid and amide ranges from 0.4:1 to 1:1.

In the preparations described in this invention, the use of methyl ester of glyoxylic acid (VIII) or its hemiacetal (IX) has a number of advantages compared to substance (III), which is used in the mentioned patents, considering that these substances are much more available and economical.

This procedure also avoids the use of hazardous solvents, such as isopropyl ether, as well as the isolation of the chlorinated compound (XI), and simplifies the procedure and removes the reaction step.

A further important difference of this invention is the use of chloroiminium salt (XIII) as a reagent for obtaining chloroester (XI).

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This reagent can be used in milder and thus more selective conditions, which is reflected in the amount of substance used and especially in the purity of the products obtained. Amide (I) was obtained in the form of colorless crystals in 73% yield during the transformation of hydroxyester (X) into ester (XII).

Sodium sulfoxylate, which is used in the reduction of the chlorinated intermediate (XI), is a simpler and more economical reagent compared to sodium borohydride.

The following non-limiting examples include exhaustive procedures that represent the operational capabilities of the present invention.

EXAMPLE 1

6-METHYL-2-(4-METHYLPHENYL)-IMIDAZO-[1,2-a]-PYRIDINE (II)

Toluene (9.4 l) is placed in a reactor with a volume of 50 l, and aluminum trichloride (3.10 kg) is added with stirring.

When the internal temperature of the suspension reaches a temperature of 0-5 °C, a solution of α-bromoacetyl bromide (2 L) in toluene (2.8 L) is added. The internal temperature must not exceed 10 °C. After the addition is complete, the internal temperature is maintained between 2 and 10 °C for 45 minutes.

Water (13.2 l) is slowly added so that the internal temperature does not exceed 50 °C, and mixing is continued for one hour. The layers are poured and separated.

The aqueous layer is removed again with toluene (3.6 l), the organic layers are combined, washed with water (5 l), 5% sodium carbonate solution (4 l), water (4 l), and finally with saturated sodium chloride solution (4 l).

It is controlled by thin-layer chromatography on a silica gel plate with a fluorescent indicator, using a mixture of benzene:ethyl acetate (9:1) as eluent.

The final organic layer, which contains the intermediate (VI, X=Br), is placed in a reactor with a volume of 50 l and heated to an internal temperature of about 30 °C. Sodium bicarbonate (2.08 kg) and a solution of 2-amino-5-methylpyridine (2.63 kg) in methanol (4.5 L) are then added.

After the addition is complete, the suspension is heated to an internal temperature of 58-62 °C and this temperature is maintained for 3 hours. It is controlled by thin-layer chromatography using the procedure described above.

After completion of the reaction, the suspension is cooled and filtered under vacuum. The solid is washed with methanol (2 × 2.5 l and 1 × 1.5 l), then with warm water (1 × 16.6 l), and finally with water at room temperature (1 × 3 l).

It is dried in an oven at 60 °C in a stream of air for 10 hours to a constant mass.

3.8 kg (70.2%) of a light yellow crystalline solid of melting point: 208-208.5 °C and 99.3% of the title compound were obtained.

1H-NMR (CDCl 3 ): δ (ppm): 7.83 (3H, d); 7.71 (1H, s); 7.51 (1H, d); 7.23 (2H, d); 6.99 (1H, dd); 2.38 (3H, s); 2.30 (3H, s).

IR (KBr) (cm-1): 3131-2860; 1645.5; 1485.4; 1423.7; 1346.5; 825.7; 806.4; 735.0.

MS (70 eV) m/e (%): 223 (16.3); 222 (100); 221 (18.9); 220 (3.4); 92 (5.9); 65 (5,1).

EXAMPLE 2

6-METHYL-2-(4-METHYLPHENYL)-IMIDAZO-[1,2-a]-PYRIDINE-3-(α-HYDROXY)-METHYL ACETATE (X)

1,2-dichloroethane (11 l) is placed in a reactor with a volume of 50 l, and intermediate (II) (3.34 kg) is added with stirring, followed by sodium acetate (0.308 kg).

A solution of methylglyoxalate (VIII) (1.6 kg) in 1,2-dichloroethane is added with stirring.

It starts heating until an internal temperature of 55 °C is reached, and is maintained under these conditions with stirring for 3 hours. It is controlled by thin-layer chromatography on a silica gel plate using a mixture of ethyl acetate:cyclohexane (6:4) as eluent.

After the end of the reaction, the reaction mixture begins to cool.

When the suspension has cooled, the solid is filtered under vacuum and washed with 1,2-dichloroethane (1 × 3.5 l and 1 × 1.5 l); and then with water (1 × 13.4 l and 1 × 3.4 l).

It is dried in an oven at 60 °C in a stream of air to a constant mass.

Decomposition yielded 4.31 kg (92.5%) of a colorless solid, melting point: 205 °C.

1H-NMR (CDCl 3 ): δ (ppm): 7.99 (1H, s); 7.53 (2H, d); 7.47 (1H, d); 7.18 (2H, d); 7.04 (1H, d); 5.80 (1H, s); 4.05-4.3 (1H, sa); 3.71 (3H, s); 2.38 (3H, s); 2.31 (3H, s).

IR (KBr) (cm-1): 3447.3; 1749.7; 1452.6; 1387.0; 1198.0; 1151.7; 1084.2; 823.7; 796.7.

MS (70 eV) m/e (%): 311 (2.0); 310 (9.0); 252 (19.7); 251 (100); 223 (3.6); 222 (2.0), 103 (1.1); 92 (4.4); 65 (2.8).

EXAMPLE 3

6-METHYL-2-(4-METHYLPHENYL)-IMIDAZO-[1,2-a]-PYRIDINE-3-(α-HYDROXY)-METHYL ACETATE (X)

Dichloromethane (260 l) is added to the 600 l reactor, followed by intermediate (II) (95 kg) with stirring, and then anhydrous sodium acetate (8.8 kg).

A solution of methyl hemiacetal from methyl glyoxalate (IX) (75 kg) (62 l) is added with stirring at room temperature.

It begins to be heated until an internal temperature of 40-42 °C is reached, and the mixture is maintained under these conditions for 4 hours with stirring. It is controlled by thin-layer chromatography on a silica gel plate using a mixture of ethyl acetate:cyclohexane (6:4) as eluent.

After the end of the reaction, the reaction mixture begins to cool down to a temperature of 5 °C.

When the suspension has cooled, the solid is centrifuged and washed with dichloromethane.

It is dried in an oven at room temperature in a stream of air.

The solid is suspended in water (355 l) at 28 °C. It is centrifuged again and washed with water. It is dried in a stream of air at 60 °C.

121.4 kg (91.5%) of the compound with the same properties as the compound from example 2 was obtained.

EXAMPLE 4

6-METHYL-2-(4-METHYLPHENYL)-IMIDAZO-[1,2-a]-PYRIDINE-3-METHYL ACETATE (XII)

Chloroform (9.6 l) and thionyl chloride (2.02 l) are added to the 50 l reactor. It is cooled to 5 °C and a solution of dimethylformamide (2.0 l) in chloroform (4.0 l) is added with stirring. The reaction is exothermic and room temperature is reached.

Continue mixing at the indicated temperature for 45 minutes from the start of the addition.

The reaction mixture is cooled to an internal temperature of 5-10 °C and, with stirring, intermediate (X) (6.0 kg) in granules is added together with 3.3 l of chloroform.

Stirring was continued at room temperature for 2 hours.

After that, granules of sodium sulfoxylate aldehyde (Rongalite) are added, and mixing is continued for 2 hours at a temperature of 38-40 °C.

It is heated to 50 °C, methanol (20 l) is added and filtered at that temperature, and the precipitate is washed well with methanol at 50 °C.

The filtrate is concentrated by distillation under reduced pressure to a volume of about 13 liters, during which the chloroform is removed with methanol.

Water (6 l) is then added, heated to 60 °C and filtered.

The filtrate is cooled to 40 °C and a 10% solution of sodium hydroxide (m/v) is added until pH 10-11 is reached.

It is cooled and filtered.

This crude, wet solid was crystallized from methanol (20 L) by hot filtration over activated carbon (0.1 kg), after which water (19 L) was added and cooled.

It is dried in an air-flow oven with a gradual increase in temperature up to 60 °C.

4.16 kg (73.1%) of solids were obtained, melting point: 133-135 °C.

1H-NMR (CDCl 3 ): δ (ppm): 7.83 (1H, s); 7.70 (2H, d); 7.55 (1H, d); 7.27 (2H, d); 7.06 (1H, dd); 4.02 (2H, s); 3.76 (3H, s); 2.40 (3H, s); 2.35 (3H, s).

IR (KBr) (cm-1): 1726.6; 1392.8; 1331.1; 1228.8; 1176.8.

MS (70 eV) m/e (%): 296 (2.0); 295 (14.0); 294 (65.5); 237 (42.6); 235 (100); 233 (10.4), 221 (2.0); 220 (11.5); 219 (20.7); 92 (31.2); 86 (8.0); 84 (11.2); 65 (16).

EXAMPLE 5

N,N,6-TRIMETHYL-2-(4-METHYLPHENYL)-IMIDAZO-[1,2-a]-PYRIDINE-3-ACETAMIDE (I)

A 39% solution of dimethylamine in ethylene glycol (m/m) (7.6 l) is added to a steel reactor with a capacity of 50 l, which is designed in such a way that it can work at elevated pressure, after which intermediate (XII) (3.125 kg) with mixing.

The apparatus is closed and heated to a temperature of 55-65 °C, while the pressure does not exceed 24.1▪104 Pa.

After 3 hours, check whether the reaction is complete using thin-layer chromatography (silica gel plates with fluorescent indicator; eluent: cyclohexane:dichloromethane:diethylamine (7:2:1)).

The suspension is cooled until the external and internal pressure equalizes, and poured into water (12 l), which is in a steel tank with five mechanical stirrers. At the end, 4 liters of water are added by pouring into the tank, and the reactor is cleaned.

The suspension is stirred at room temperature for about 2 hours.

It is cooled to 10 °C, filtered and washed with water (2 × 3 l).

The obtained product is dried in an oven at 60 °C in a stream of air to a constant mass.

The crude solid is recrystallized from acetonitrile (17 L).

It is cooled, filtered, washed and dried in an oven at 60 °C in a stream of air to a constant mass.

2.84 kg (87%) of colorless product was obtained, melting point: 195-197 °C.

1H-NMR (CDCl 3 ): δ (ppm): 7.98 (1H, s); 7.55 (2H, d); 7.52 (1H, d); 7.26 (2H, d); 7.04 (1H, dd); 4.07 (2H, s); 2.94 (3H, s); 2.88 (3H, s); 2.40 (3H, s), 2.35 (3H, s).

13C-NMR (CDCl3) (splitting 1H):

166,161; 143,959; 143,682; 137,187; 131,717; 129,139; 128,217; 127,230; 121,990; 121,449; 116,355; 113,560; ; 37,288; 35,632; 29,973; 21,079; 18,249.

IR (KBr) (cm-1): 2980-3005; 1635.9; 1138.2; 825.7; 794.8.

MS (70 eV) m/e (%): 309 (5.0); 308 (41.2); 307 (100); 236 (68.2); 235 (71.9); 233 (22.9), 222 (2.1); 221 (4.8); 220 (27.4); 219 (51.4); 92 (51.6); 65 (37.9).

ELEMENTARY ANALYSIS:

OBTAINED: C: 74.36% H: 6.92% N: 13.56%

CALCULATED: C: 74.24% H: 6.89% N: 13.67%

EXAMPLE 5

N,N,6-TRIMETHYL-2-(4-METHYLPHENYL)-IMIDAZO-[1,2-a]-PYRIDINE-3-ACETAMIDE-[R-(R*,R*)]-2,3-DIHYDROXYBUTANIOATE ( 2:1)

Methanol (25 l) and substance (I) (2.44 kg) are added to the 50 l reactor.

It is heated until it dissolves and a solution of L-(+)-tartaric acid (0.6 kg) in methanol (4.5 l) is added.

It is concentrated by distillation until a volume of about 18 l is obtained, cooled, filtered and washed with the same solvent.

The product is dried in a stream of air with a gradual increase in temperature to about 60 °C.

2.82 kg (93%) of the reference compound were obtained, melting point: 193-195 °C.

IR (KBr) (cm-1): 1645.5; 1404.4; 1344, 6; 1275.1; 1147.8; 1138. 2; 1115.0; 1076.4; 1022.4; 918.3; 825.7; 794.8; 719.6; 621.2; 600.0.

ELEMENTARY ANALYSIS:

OBTAINED: C: 66.06% H: 6.32% N: 10.95%

CALCULATED: C: 65.97% H: 6.28% N: 10.99%

Claims (5)

1. Preparation procedure of N,N,6-trimethyl-2-(4-methylphenyl)-imidazo-[1,2-a]-pyridine-3-acetamide of formula (I): [image] characterized in that it involves the reduction of a hydroxyester of formula (X) [image] in the reaction that takes place in DMF, and then with the iminium salt of formula (XIII), which is formed in situ with the help of thionyl chloride and dimethylformamide, [image] , as well as the subsequent reduction with the help of a suitable reducing agent to form the ester of formula (XII), [image] which is then reacted with dimethylamine in a polyhydroxylated solvent, at the appropriate temperature. 2. The method according to claim 1, characterized in that the specified appropriate reducing agent, by which the ester of formula (XII) is formed, is selected from sodium sulfoxylate formaldehyde or sodium hydrosulfite, after which the specified ester reacts with dimethylamine in a polyhydroxylated solvent, such as ethylene glycol or propylene glycol, at a temperature ranging from 30 to 70 °C. 3. The method according to claim 1, characterized in that the mentioned 6-methyl-2-(4-methylphenyl)-imidazo-[1,2-a]-pyridine-3-(α-hydroxy)-methylacetate of the formula (X) is obtained by the reaction of compound (II) and methylglyoxalate of formula (VIII) or its hemiacetal of formula (IX) [image] [image] in a chlorinated solvent, such as chloroform, 1,2-dichloroethane or trichloroethylene, at a temperature of 40 to 70 °C. 4. The method according to claim 2, characterized in that said 6-methyl-2-(4-methylphenyl)-imidazo-[1,2-a]-pyridine of formula (II) is the reaction product of 2-amino-5-methyl-pyridine of formula (V) and α-halo-4-methyl acetophenone of formula (VI) (X = Cl or Br) [image] in toluene and an alcohol containing from one to three carbon atoms, with the addition of a base, such as sodium bicarbonate or potassium bicarbonate, at an operating temperature of 40 to 70 °C. 5. The method according to any of the preceding claims, characterized in that the free base of formula (I) reacts with an acid, such as tartaric acid, oxalic acid or acetic acid, in an alcoholic medium, in which methanol, ethanol or isopropanol is used as a solvent , with a molar ratio of acid and base in the amount of 0.4:1 and 1:1, and that the corresponding salt crystallizes with a degree of purity suitable for use in human medicine.